Opinion statementNontuberculous mycobacteria (NTM) are found in approximately 10 % of cystic fibrosis (CF) patients, but only a portion will develop NTM disease. The management of CF lung disease should be optimized, including antibiotic therapy targeted to the individual’s usual airway bacteria, prior to considering treatment for NTM lung disease. Those who meet criteria for NTM lung disease may not necessarily require treatment and could be monitored expectantly if symptoms and radiographic findings are minimal. However, the presence of Mycobacterium abscessus complex (MABSC), severe lung disease, and/or anticipated lung transplant should prompt NTM therapy initiation. For CF patients with Mycobacterium avium complex (MAC), recommended treatment includes triple antibiotic therapy with a macrolide, rifampin, and ethambutol. Azithromycin is generally our preferred macrolide in CF as it is better tolerated and has fewer drug-drug interactions. MABSC treatment is more complex and requires an induction phase (oral macrolide and two IV agents including amikacin) as well as a maintenance phase (nebulized amikacin and two to three oral antibiotics including a macrolide). The induction phase may range from one to three months (depending on infection severity, treatment response, and medication tolerability). For both MAC and MABSC, treatment duration is extended 1-year post-culture conversion. However, in patients who do not achieve culture negative status but tolerate therapy, we consider ongoing treatment for mycobacterial suppression and prevention of disease progression.
Despite their similar semen parameters, infertile men with normal karyotypes displayed more frequent increases in sperm aneuploidy, particularly involving the sex chromosomes, than infertile men who were carriers of chromosomal rearrangements. The difference in the magnitude and type of sperm aneuploidy between the two infertile groups is likely related to the different causes of infertility.
Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8-16 micrograms/kg/day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GM-CSF day +21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24-32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm3) at day +11 and ANC greater than 500/mm3 at day +16. Optimal dose of G-CSF and GM-CSF to stimulate neutrophil recovery post transplant was 4-8 micrograms/kg/day and 8-16 micrograms/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.
RationaleC-reactive protein (CRP) is a systemic marker of inflammation that correlates with disease status in cystic fibrosis (CF). The clinical utility of CRP measurement to guide pulmonary exacerbation (PEx) treatment decisions remains uncertain.ObjectivesTo determine whether monitoring CRP during PEx treatment can be used to predict treatment response. We hypothesized that early changes in CRP can be used to predict treatment response.MethodsWe reviewed all PEx events requiring hospitalization for intravenous (IV) antibiotics over 2 years at our institution. 83 PEx events met our eligibility criteria. CRP levels from admission to day 5 were evaluated to predict treatment non-response, using a modified version of a prior published composite definition. CRP was also evaluated to predict time until next exacerbation (TUNE).Measurements and main results53% of 83 PEx events were classified as treatment non-response. Paradoxically, 24% of PEx events were characterized by a ≥ 50% increase in CRP levels within the first five days of treatment. Absolute change in CRP from admission to day 5 was not associated with treatment non-response (p = 0.58). Adjusted for FEV1% predicted, admission log10 CRP was associated with treatment non-response (OR: 2.39; 95% CI: 1.14 to 5.91; p = 0.03) and shorter TUNE (HR: 1.60; 95% CI: 1.13 to 2.27; p = 0.008). The area under the receiver operating characteristics (ROC) curve of admission CRP to predict treatment non-response was 0.72 (95% CI 0.61–0.83; p<0.001). 23% of PEx events were characterized by an admission CRP of > 75 mg/L with a specificity of 90% for treatment non-response.ConclusionsAdmission CRP predicts treatment non-response and time until next exacerbation. A very elevated admission CRP (>75mg/L) is highly specific for treatment non-response and might be used to target high-risk patients for future interventional studies aimed at improving exacerbation outcomes.
Purpose Complex chromosomal rearrangements (CCR) are rare rearrangements involving more than two chromosomes and more than two breakpoints. CCR are associated with male infertility as a result of the disruption of spermatogenesis due to complex meiotic configurations and the production of chromosomally abnormal sperm. We examined a carrier of a t(1:2:10) CCR in order to determine the patterns of segregation and any presence of an interchromosomal effect (ICE). Methods Centromeric, locus specific and telomeric probes (Vysis, USA) were used for the study. On~1,000 sperm nuclei from the reciprocal translocation carrier, dual color Fluorescence in situ hybridization (FISH) was performed on each of the involved chromosomes to determine the patterns of segregation. FISH was also performed on chromosome 13, 18, 21, X and Y to determine any ICE. Results We observed abnormal chromosome complements in 24.3%, 19.5% and 15.8% of sperm for chromosomes 2, 10 and 1, respectively. There was a significantly increased rate of ICEs for chromosomes 13 and 21 when compared with controls. Conclusions CCR may present a lower risk for producing unbalanced chromosomes than other studies have indicated.CCRs may be at an increased risk for ICE especially among acrocentric chromosomes.
Disrupted meiotic behaviour of inversion carriers may be responsible for suboptimal sperm parameters in these carriers. This study investigated meiotic recombination, synapsis, transcriptional silencing and chromosome segregation effects in a pericentric inv(1) carrier. Recombination (MLH1), synapsis (SYCP1, SYCP3) and transcriptional inactivation (γH2AX, BRCA1) were examined by fluorescence immunostaining. Chromosome specific rates of recombination were determined by fluorescence in-situ hybridization. Furthermore, testicular sperm was examined for aneuploidy and segregation of the inv(1). Our findings showed that global recombination rates were similar to controls. Recombination on the inv(1) and the sex chromosomes were reduced. The inv(1) associated with the XY body in 43.4% of cells, in which XY recombination was disproportionately absent, and 94.3% of cells displayed asynapsed regions which displayed meiotic silencing regardless of their association with the XY body. Furthermore, a low frequency of chromosomal imbalance was observed in spermatozoa (3.4%). Our results suggest that certain inversion carriers may display unimpaired global recombination and impaired recombination on the involved and the sex chromosomes during meiosis. Asynapsis or inversion-loop formation in the inverted region may be responsible for impaired spermatogenesis and may prevent sperm-chromosome imbalance.
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